Study of the paraneoplastic neurologic disorders (PNDs) offers a unique opportunity to study cellular mechanisms of naturally occurring tumor immunity in humans. PND patients harbor systemic tumors expressing proteins normally made only in neurons. Perhaps in part because of this restriction to immune privileged sites, ectopic expression of these proteins in tumors is believed to result in a potent tumor immune response and clinically evident tumor suppression. We have studied the tumor immune response in patients with paraneoplastic cerebellar degeneration (PCD). PCD patients develop tumor immunity to breast or ovarian cancers that express a Purkinje neuronal protein termed cdr2. In preliminary experiments we have identified cdr2-specific CTLs in the peripheral blood of 5/5 HLA- A2.1+PCD patients. These data suggest a cellular basis for the tumor immunity in PCD. We plan to confirm and extend these observations by using a variety of methodologies to detect antigen-specific CTLs in PND patients. We have been able to detect cdr2-specific CTLs using apoptotic cdr2 expressing cell line as the source of antigen, and will examine whether apoptotic antigen expressing tumor cell lines can efficiently serve as the source of antigen for presentation to autologous DCs. We will extend these studies to a new antigen, Hu, targeted in PND patients with small cell lung cancer. We will also explore the role that CD4 cell help plays in triggering effective tumor immunity in PND. Finally, we have found that PND antigens are expressed in a high percentage of tumors obtained from neurologically normal cancer patients. We will examine whether some such patients harbor antigen-specific CTLs and have tumor immunity. Moreover, we will test the hypothesis that three different clinically important sets of cancer patients with PND antigen-expressing tumors can be distinguished in the laboratory; those without tumor immune responses, who we hypothesize have tolerized CTL responses and absent CD4 helper responses, those with tumor immunity in the absence of neurologic disease, who have both CTL and CD4 helper responses, and those with PND, who have broken immune tolerance to neuronal antigens expressed in the brain. These experiments offer the possibility of developing new cancer treatments and advancing the understanding of autoimmune disease of the nervous system.